A functional folate receptor is induced during macrophage activation and can be used to target drugs to activated macrophages.
Previous work has demonstrated that a subset of macrophages expresses a folate receptor (FR) that can mediate internalization of folate-linked molecules, including imaging and therapeutic agents. To characterize this subset, macrophages were collected from peritoneal cavities of mice injected with saline, thioglycolate, zymosan, heat-killed or live bacteria, and cell-surface markers that coexpress with FR were identified. Virtually no F4/80(+) peritoneal macrophages from saline-injected mice expressed FR, whereas numerous macrophages from mice injected with each inflammatory stimulus expressed FR. Examination of cell differentiation antigens that are up-regulated in FR(+) macrophages revealed markers characteristic of an activated state (CD80, CD86, Ly-6C/G), whereas macrophages lacking these activation markers expressed few or no FR. FR(+) macrophages also produced tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species, and production of reactive oxygen species correlated linearly with expression of FR. Synovial macrophages collected from arthritic patients were found to bind and internalize folate-linked dyes. Moreover, a folate-linked radioimaging agent was shown to image inflamed joints of rheumatoid arthritic patients. These results suggest that FR constitutes a marker for macrophage activation and that FR(+) macrophages can be targeted with folate-linked drugs without promoting drug uptake by nonactivated macrophages. This trial was registered at www.clinicaltrials.gov as #NCT00588393.
Xia
Wei
W
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Hilgenbrink
Andrew R
AR
Matteson
Eric L
EL
Lockwood
Michael B
MB
Cheng
Ji-Xin
JX
Low
Philip S
PS
D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis*; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage; D011859:Radiography; D011877:Radionuclide Imaging / Q000379:methods; D019275:Radiopharmaceuticals / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; D002352:Carrier Proteins; C473829:EC20 folate peptide; D058973:Folate Receptors, GPI-Anchored; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D005492:Folic Acid